DESCRIPTION: This is a competing renewal application which focuses on the signaling specificity of the insulin receptor kinase. The insulin receptor is regulated by several mechanisms including insulin binding, tyrosine autophosphorylation, interactions with substrates and serine phosphorylation. A full understanding of the insulin signaling system and the elements it interacts with is scientifically and clinically important because diabetes is a contemporary health problem that affect millions of Americans. Diabetes mellitus results from either a lack of insulin (type I diabetes or IDDM) or the failure to compensate for a diminished insulin response at various target tissues (type II diabetes or NIDDM). While there are important differences between IDDM and NIDDM, both diseases are characterized by high levels of circulating glucose and both are accompanied in the long term by a set of debilitating sequelae, including retinopathy, nephropathy, neuropathy and vascular disease. The principle causes of NIDDM have been difficult to discover by genetic means since NIDDM appears to result from a complex set of genetic and environmental inputs. Thus, a molecular understanding of the cellular mechanism of insulin action and its regulation will ultimately elucidate the pathophysiology of NIDDM and may lead to the design of efficacious interventions. This proposal tests the applicant's original hypothesis put forward several years ago that insulin signaling requires correct substrate selection and selective tyrosine phosphorylation. The Specific Aims will explore three areas: (1) Substrate interactions with the catalytic domain of the insulin receptor kinase; (2) The role of PTP domains for coupling substrates to the insulin receptor kinase; and (3) The structure and function of pp60irs: a PTP-protein substrate of the insulin receptor in adipocytes.